Rod/cone gap junctions initiate an irradiance pathway

杆/锥间隙连接启动辐照度路径

• 批准号: 10441265
• 负责人: STEPHEN C MASSEY
• 金额: $ 51.96万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441265
• 关键词: Address; Amacrine Cells; Behavior; Behavioral; Biological; Brain; Cell Nucleus; Cell physiology; Cells; Cone; Conscious; Coupling; Data; Development; Dopamine; Electroretinography; Elements; Eye Development; Gap Junctions; Goals; Image; Inner Plexiform Layer; Intervention; Intrinsic drive; Knockout Mice; Knowledge; Lead; Life; Light; Lighting; Link; Masks; Measures; Mediating; Migraine; Mus; Myopia; Output; Pain; Pathway interactions; Photosensitivity; Play; Pupil light reflex; Retina; Retinal Ganglion Cells; Rod; Seasonal Affective Disorder; Signal Pathway; Signal Transduction; Stratification; Synapses; Testing; Travel; Vertebrate Photoreceptors; Vision; Visual; Visual system structure; cell type; circadian; circadian pacemaker; daily functioning; light intensity; melanopsin; novel; novel strategies; preservation; response; retinal rods; ribbon synapse; sensory system; suprachiasmatic nucleus; visual information; visual process

Intrinsically photosensitive retinal ganglion cells (ipRGCs) play a key role in transmitting non-image-forming visual information to the brain. Recent evidence has implicated ipRGCs in conscious vision as well as in serious conditions such as migraine pain and seasonal affective disorder. Despite the fundamental importance of ipRGCs in the visual process, the underlying synaptic mechanisms and circuits that control ipRGC function are unknown. IpRGCs express their own photopigment - melanopsin and, at high light intensities, intrinsic responses drive ipRGC function. However, surprisingly, at lower intensities, even in the photopic range, ipRGCs are predominantly driven by rods and not cones. These data suggest that a sustained signal originating from rods must travel through the retina to carry information about irradiance to ipRGCs. In this proposal, we will test the primary hypothesis that the irradiance pathway through the mammalian retina is driven via rod-to-cone gap junctions. Our preliminary studies provide evidence that a novel irradiance pathway contains the following elements: rod→rod/cone gap junction→cone→ON cone bipolar cell→ectopic synapse→M1-type ipRGCs and dopaminergic amacrine cells (DACs). In turn, M1 ipRGCs drive non-image-forming visual behavior such as the pupillary light reflex and circadian photoentrainment, while dopamine release may control network adaptation in the retina. To test these hypotheses, we have developed and validated several mouse lines in which Cx36 has been conditionally deleted in either rods or cones, and therefore lack rod/cone gap junctions. In Aim 1, we will test the hypothesis that rod/cone gap junctions are required to drive the PLR, circadian photoentrainment and negative masking, non-imaging-forming visual functions also driven by M1 ipRGCs. In Aim 2, we will test the hypothesis that rod/cone gap junctions are also essential for the release of dopamine, in the mammalian retina. Furthermore, we will test the hypothesis that dopamine-dependent network adaptation relies on the irradiance pathway via rod/cone gap junctions. In Aim 3, we will test the function of the irradiance pathway at two key points: rod/cone gap junctions and ectopic bipolar synapses in the inner plexiform layer. In summary, we propose that rod/cone coupling generates an irradiance signal transmitted via ipRGCs that not only controls the pupillary light reflex, it also entrains the circadian clock every day. The biological influence of the circadian clock is pervasive yet it may be driven via gap junctions between the first two cell types in the visual system. Furthermore, there is a link between dopamine and myopia. If, in turn, the irradiance pathway controls dopamine release, this may inform a new approach to myopia.

固有的光敏性视网膜神经节细胞(IpRGC)在传递非成像的过程中起着关键作用 视觉信息传到大脑。最近的证据表明ipRGC在有意识的视觉中以及在 严重的情况，如偏头痛和季节性情感障碍。尽管根本性的重要性 视觉加工中的ipRGC，控制ipRGC功能的潜在突触机制和电路 都是未知的。IpRGC表达它们自己的光色素--黑色素，在高光强下，固有的 响应驱动ipRGC功能。然而，令人惊讶的是，在较低的强度下，即使在明视范围内， IpRGC主要由视杆而不是视锥驱动。这些数据表明，一个持续的信号 从视杆发出的信号必须通过视网膜将有关辐射的信息传递给ipRGC。在这 提议，我们将检验通过哺乳动物视网膜的辐射途径是 通过杆-锥间隙连接驱动。 我们的初步研究提供了证据，证明一种新的辐照途径包含以下元素： Rod→视杆/视锥缝隙连接→视锥→on视锥双极细胞→异位突触→M1型ipRGC和 多巴胺能无长突细胞(DAC)。反过来，M1 ipRGC驱动非图像形成的视觉行为，如 瞳孔光反射和昼夜节律性光携带，而多巴胺释放可能控制网络适应 在视网膜上。为了验证这些假设，我们开发并验证了几个Cx36小鼠品系 在杆或锥中被有条件地删除，因此缺少杆/锥间隙连接。 在目标1中，我们将测试杆/锥体间隙连接是驱动PLR的假设，昼夜节律 光捕获和负掩蔽，非成像的视觉功能也由M1的ipRGC驱动。 在目标2中，我们将检验杆状/锥体缝隙连接对多巴胺释放也是必不可少的假设， 在哺乳动物的视网膜中。此外，我们将测试多巴胺依赖网络的假设 适应依赖于通过视杆/视锥缝隙连接的辐射途径。 在目标3中，我们将在两个关键点测试辐射途径的功能：杆/锥缝隙连接和 内网状层的异位双极突触。 综上所述，我们认为棒/锥耦合产生的辐射信号通过ipRGC传输，而不是 它不仅控制着瞳孔的光反射，它还牵连着每天的生物钟。病毒的生物学影响 生物钟是普遍存在的，但它可能是通过 视觉系统。此外，多巴胺和近视之间存在联系。如果，反过来，辐射途径 控制多巴胺的释放，这可能为治疗近视提供一种新的方法。